Vaccines and Therapeutics for Nipah and Hendra virus

描述(申请人提供)：广泛的物种趋向性和在动物和人类中引起致命疾病的能力使Henipah病毒、Nipah病毒(Niv)和Hendra病毒(HEV)有别于所有其他已知的副粘病毒。这些病毒可以被放大，在动物身上引起疾病，并传播给人类，在人类感染表现为严重的呼吸道疾病和/或发热性脑炎。它们被归类为BSL-4选择性毒剂，并具有使其高度适应用作生物恐怖毒剂的几个特点。HEV于1994年首次出现在澳大利亚，并通过受感染的马匹传播给人类；新城疫病毒于1998-99年出现在马来西亚，主要是从受感染的猪传播给人类，但也有几种动物被感染。这两种病毒继续重新出现；2004年，孟加拉国的两起新城疫疫情造成约65例人间病例。2005年在同一地区爆发的另一次疫情夺走了12人的生命，2007年印度最近出现的疫情夺走了5人的生命。1999年、2004年和2006年，HEV在澳大利亚再次出现，出现了马匹致命感染病例和一例非致命性血清转换人间病例。公共卫生相关性：在最近的新城疫疫情中，重要的观察结果是急性呼吸窘迫综合征的发病率较高，人与人之间的传播，病死率较高(约75%)，与受感染的牲畜或家畜无关。现在，开发治疗学和疫苗策略是重要的。在过去的几年里，我们对病毒包膜糖蛋白(F和G)、病毒组装机制进行了广泛的表征，开发了病毒融合抑制剂，并确定了HEV和NIV的细胞受体(EwitinB2)。最近，我们已经鉴定了一种可溶性G糖蛋白(SG)作为亚单位疫苗，作为新城疫病毒感染的猫模型，并证明了SG对新城疫病毒的攻击具有保护作用。我们还分离和鉴定了有效的中和全人抗G单抗，并绘制了G上的受体结合部位图。本建议的目的是：充分表征Nipah病毒感染的雪貂模型，并评估现有的治疗Nipah和Hendra病毒感染的新方法。具体目的是：1)在雪貂模型中建立新城疫病毒的感染、致死剂量和检测参数。2)评价SG作为新城疫亚单位疫苗对雪貂的保护效果。3)确定中和、抗G、全人单抗治疗对猫和雪貂新城疫病毒感染的被动保护效果。4)确定Niv SG与其受体ewitinB2的络合物的溶液结构，并进行结构依赖性设计和结构非依赖性高通量筛选发现G受体相互作用的小分子抑制剂。

DESCRIPTION (provided by applicant): The broad species tropisms and the ability to cause fatal disease in both animals and humans have distinguished the Henipaviruses; Nipah virus (NiV) and Hendra virus (HeV) from all other known paramyxoviruses. These viruses can be amplified and cause disease in animals and be transmitted to humans where infection is manifested as a severe respiratory illness and/or febrile encephalitis. They are classified as BSL-4 select agents and possess several characteristics which make them highly adaptable for their use as bioterror agents. HeV appeared first in Australia in 1994 and was transmitted to humans from infected horses; NiV appeared in 1998-99 in Malaysia and was predominantly passed from infected pigs to humans, but several animal species were also infected. Both viruses continue to re-emerge; in 2004 two NiV outbreaks in Bangladesh caused some 65 human cases. Another outbreak in 2005 in the same area claimed 12 lives, and a recent emergence in India in 2007 has taken 5 lives. HeV has reappeared in Australia in 1999, 2004 and 2006, with cases of fatal infection in horses and one non-fatal, sero-converting, human case. Public health relevance: Significant observations in the most recent NiV outbreaks have been a higher incidence of acute respiratory distress syndrome, person-to-person transmission, higher case fatality rates (~75%), and no link to infected livestock or domestic animals. The development of therapeutics and vaccine strategies is now important. Over the past several years we have performed an extensive characterization of the viral envelope glycoproteins (F and G), virus assembly mechanisms, developed viral fusion inhibitors and identified the cellular receptor for both HeV and NiV (ephrinB2). Recently, we have characterized a soluble G glycoprotein (sG) as a subunit vaccine, a cat model for NiV infection and have demonstrated that sG can protect against NiV challenge. We have also isolated and characterized potent neutralizing fully-human anti- G monoclonal antibodies and have mapped the receptor binding site on G. The objectives of this proposal are to: fully characterize a ferret model of Nipah virus infection, and evaluate existing and discover new therapeutic modalities for treating Nipah and Hendra virus infection. The Specific Aims are: 1) Establish virus infection, lethal dose, and detection parameters of NiV in a ferret model. 2) Evaluate the protective efficacy of sG as a subunit vaccine for NiV in the ferret. 3) Determine the passive protective efficacy of neutralizing, anti-G, fully-human monoclonal antibody therapy for NiV infection in the cat and ferret. 4) Determine the solution structure of NiV sG in complex with its receptor ephrinB2, and perform both structure-dependent design and structure-independent High-Throughput-Screening discovery of small- molecule inhibitors of the G-receptor interaction.